Substituted amino analogs of pantothenic acid and process



Patented Oct. 16, 1951 SUBSTITUTED ADIINO ANALOGS OF PANTO- I THENIC ACID AND PROCESS Karl Folkers, Plainfield, and Frederick W. Holly, Cranford, N. J., asslgnors to Merck & 00., Inc., Rahway, N. J a corporation of New Jersey No Drawing. Application April 20, 1949,

Serial No. 88,697

13 Claims; (Cl. 260482) 1 2 This invention relates to new physiologically ness in stimulating the growth of bacteria. For active substances having a vitamin-like action, example, the amino analog, ethyl pV-(a-aminoand, more particularly, to amino analogs and 5,5 dimethyl 'y hydroxybutyrylamino) prosubstituted amino analogs of pantothenic acid. pionate was assayed for 'pantothenic acid activity Pantothenic acid has a structure corresponding 5 for Lactobacillus arabinosus. On investigation, to the following formula: it was found that when an amount of pantothenic acid sufficient to yield one-half maximum growth (Crime-03mmONHCHCHCOOH was mixed with an equal quantity of the analog H1011 (0.02 mi'crogram of each compound/10 ml. of

while the amino analog and substituted amino growth resulted; analogs of pantothenic acid may be represented UP to the f of plfesent dlsclosm'el mm bythe fonowmg general formula: of the physiologically actlve compounds represented by the formula, supra, have either been NHR synthesized or isolated from natural sources. In came-( inoonncmcmcoon" l5 accordance with this disclosure, members of this HOR, roup of compounds have now been prepared synthetically and identified. It may be noted wherein R represents a member selected from the that the e-amino-y-butyrolactones and derivagroup consisting of hydrogen, an acyl radical, and tives thereof, more fully described in our copenda carbobenzoxy radical, R represents a member 20 lng application Serial No. 88,696, filed April 20, selected from the o p consisting of hydrogen 1949, are used as intermediates in the preparaand an acyl radical and R" represents a member tion of this group of compounds. selected from the group consisting of alkyl and Reactions for the preparation of ethyl 5'4- aralkyl radicals. amino 5,5 dimethyl 'y hydroxybutyryl- These compounds are not only structurally 25 amino) -propionate and the other members of this similar to pantothenic acid but are also similar group of compounds may be represented by the in function thereto having shown their effectivefollowing equations:

H1 0 O Ethyl-fi-amlno- OH; OH \0/ propionate Ethyl fi- (wearbobenzoxyamino B, a- Carbobenzoxyamino afi-dimethyl-y- B-dlmeth yl-y-hydroxybutyrylamino) butyrolactone proplonate I II Hydrogenolysls NHz.H Cl

Pd-C (CH.-.)2CJJHCONHCH1CH1C0102B: Compound II 1101 HOH Ethyl p-(a-amlno-fi,B-dl!nethyl- -hydroxybutyrylamino) -proplonate hydro-chloride NHcoom Compound m cmco o crmiotmconnomcmoozczm H200 OCH:

Ethyl B- (a-cetylamlno-Bfi-dlmethyl,- acetoxybutyrylamlno) -propi0nate NH O 0 CH: )zCCHNHCO OH; NHaCHzCHzC OzCzHs (CHs)zC-( JHC ONHCHzCHzC ()zCzHs CH: O Ethyl Baminoprooionate H2 0 H butyrolactone hydroxy-butyrylamino)-propionate mm cm Preparations of representative members of this new class of compounds will be illustrated in greater detail in the following examples, in which their synthesis from readily obtainable intermediates is described. It is to be understood that these examples are given by way of illustration and not to be considered as limiting the invention to the particular details described therein.

EXAMPLEI Ethyl o'-(a-carbobenzoxyamino-p,p-dimethyl-- hyclroxybutyrylamino) -propionatc 0.01 mm. for 5 minutes.

On analysis, the following results were obtained:

Calculated for Found C mHzaNzOe Nitrogen I 7. 37 7. 49

EXAMPLE II Ethyl p-(a-ami120-p,s-dimethyl--y-hydrozrybutyrylamino) -propionate hydrochloride The carbobenzoxy group of the p-alanine derivative prepared in Example I, supra, was removed by hydrogenolysis of the compound over a palladium-charcoal catalyst in ethanolhydrochloric acid solution. This reaction yielded the hydrochloride of the amino analog of pantothenic acid as an ethyl ester and is described in detail as follows:

A solution of 7.5 g. (0.02 mole) of ethyl B'-(- carbobenzoxyamino-p,p-dimethyl 'y hydroxybutyrylamino)-propionate in '15 ml. of ethanol containing 2 ml. of concentrated hydrochloric acid was hydrogenated over 8 g. of a palladium- Darco catalyst (5% palladium-prepared as shown in Organic Syntheses, vol. 26, page '78, procedure B) for 1.6 hours, during which time 0.016 mole of hydrogen was absorbed. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to an oil containing ethyl p-(a-amino-B,fl-dimethyl-' -hydroxybutyrylamino) -propionate hydrochloride.

Although it was found convenient to isolate ethyl B'-(a-amino-.8,Bdimethyl 'y hydroxybutyrylamino) -propionate in the form of its hydrochloride salt, it is apparent to those skilled in the art that the free base can be obtained from the salt by conventional methods.

EXAMPLE III Ethyl p-(a-acetylamlno-ap-dimethylacetoxybutmlamino) -propionate A 1.5 g. sample of the oil obtained in Example 11 containing ethyl p'-(a-amino-fi,fl-dimethyl--yhydroxybutyrylamino) -propionate hydrochloride was heated for 5 minutes at 90 C. in a mixture of acetic anhydride and pyridine and then concentrated under reduced pressure. The oily residue was dissolved in 50 ml. of chloroform and washed twice with 25 ml. of water. Evaporation of the chloroform yielded a crystalline product that was recrystallized from chloroform-ether. There was obtained 0.9 g. of ethyl p'-(a-acetylamino-p,pdimethyl-'y-acetoxybutyrylamino) propionate, M. P.: 128-129 (micro-block). This diacetyl derivative has the same melting point and infrared absorption spectrum as another sample of the diacetyl derivative which had been synthesized by alternative reactions.

EXAMPLEIV' Ethyl p-(a-acetylaminO-Bfi-dimethyZ-yhydroxybutyrylamino) -propionate A mixture of 3.4 g. of a-acetylamino-p,p-di- 'methyl-v-butyrolactone and 2.6 g. of ethyl C lculated for xa 24N2O5 Found EXAIHPLE V Ethyl o'-(a-acetylamino-,e,,e-dimethyZ-yacetoxybutyrylamino) -propionate I 2 g. of ethyl B-(a-acetylamino-fi,B-dimethylhydroxybutyrylamino)-propionate was added to a solution of 15 ml. of acetic anhydride and 12 ml. of pyridine, and the mixture was heated on a steam bath for 5 minutes. The solution was concentrated in vacuo to a crystalline residue which was recrystallized 4 times from a mixture of chloroform and ether to give 1 g. of ethyl n- (a-acetylamino-c,;3-dimethyl -Y- acetoxybutyrylamino)-propionate, M. P. 127-128 (microblock). On analysis, the following results were obtained:

Calculated for cimtmot X Ebullioscapic in benzene.

III; in column B are the bands for the product 01' Example V. Only strong bands were recorded. INFRA-RED ABSORPTION DATA Various changes and modifications maybe 6 zoxyamino 5,5 dimethyl 'y hydroxybutyrylamino)-propionate and ethanol-hydrochloric acid in the presence of a palladium-carbon catalyst and separating and recovering the thusproducedethyl ester.

8. The process for preparing ethyl (a-amino 5,5-dimethyl 'y hydroxybutyrylamino) bro- I pionate which comprises the hydrogenolysis of a. solution containing ethyl 5'-(a-carbobenzoxy- 'amino-5,5-dimethyl 7 hydroxybutyrylamino) propionate and ethanol-hydrochloric acid in the presence of a 5% palladium-carbon catalyst and separating and recovering the thus-produced ethyl ester.

9. A method for the preparation of ethyl 5'- (a acetylamino-5,5-dimethyl-v-acetoxybutyrylamino) -propionate which comprises inter-reacting a carbobenzoxyamino 5,5 dimethyl-'y-butyrolactone and ethyl-p-amino propionate, submade in carrying out the present invention with-' out departing from the spirit and scope thereof. Insofar as these changes and modifications are within the scope of the appended claims, they are to be considered as part of this invention.

We claim:

1. As anew physiologically active chemical compound ethyl 5-(c-amino 5,5 dimethyl 'y hydroxybutyrylamino) propionate and strong mineral acid salts thereof.

2. As a new chemical compound ethyl 5-(- carbobenzoxyamino -5,5- dimethyl 7 hydroxybutyrylamino) -propionate.

3. As a new chemical compound ethyl 5'-(- acetylamino 1 5 dimethyl -y acetoxybutyrylamino) -propionate.

4. A method for synthesizing ethyl. 5'-(- amino-5,5-dimethy1 Y hydroxybutyrylamino) propionate which comprises inter-reacting a.- carbobenzoxyamino 5.5 dimethyl-Y-butyrolactone and ethyl-5-amino propionate, subjecting the resulting ethyl 5'-(a-carbobenzoxyamino-5,5- dimethyl-Y-hydroxybutyrylamino) -propionate to hydrogenolysis, and recovering the ethyl 5'- (a amino 5,5 dimethyl 7 hydroxybutyryl amino) -propionate thus formed.

'5. A method for synthesizing ethyl fi'-(aamino-5,5-dimethyl 'y hydroxybutyrylami'no) propionate which comprises inter-reacting o.- carbobenzoxyamino 5,5 dimethyl 'y butyrolactone and ethy1-5-amino propionate, subjecting the resulting ethyl 5'-(a-carbobenzoxyamino-5,5-

dimethyl-v-hydroxybutyrylamino) -propionate to hydrogenolysis using a palladium-charcoal catalyst in an ethanol-hydrochloric acid medium, and

recovering the ethyl 5'-(-amino-5,5'-dimethylhydroxybutyrylamino) -propionate thus formed. 6. The process for preparing ethyl 5'-(c-amino- 5,5-dimethyl-'y hydroxybutyrylamino) propionate which comprises the hydrogenolysis of ethyl 5-(a-carbobenzoxyammo-pp-dimethyl v hydroxybutyrylamino) -propionate in an acidified alcoholicmedium and separating and recovering the thus-produced ethyl ester.

7. The process for preparing ethyl p'-(- amino-5,5-dimethyl hydroxybutyrylamino) propionate which comprises the hydrogenolysis of a solution containing ethyl p'-(-carbobenjecting the resulting ethyl 5-(a-carbobenzoxyamino-5,5-dimethyl 'y hydroxybutyrylamino) propionate to hydrogenolysis to obtain ethyl 5'- (a acetylamino-5,5-dimethyl-'y-acetoxybutyrylamino) -propionate hydrochloride, and treating the same with acetic anhydride to form ethyl 5'- (a. acetylamino-5,5-dimethyl-'y-acetoxybutyrylamino) -propionate.

10. A method for the preparation of ethyl 5'- (a. acetylamino-5,5-dimethyl-'y-acetoxybutyrylamino)-propionate which comprises inter-reacting a carbobenzoxyamino 5,5 dimethyI- -butyrolactone with ethyl-5-amino propionate, subjecting to hydrogenolysis in an ethanol-hydrochloric acid medium the resulting product, ethyl 5'-(a-carbobenzoxyamino-.5,5-dimethyl '1 hydroxybutyrylamino) -propionate to obtain ethyl 5'-(-amino-5,5 dimethyl v hydroxybutyrylamino) -propionate hydrochloride, treating the same'with acetic anhydride in a pyridine solution and recovering the ethyl 5'-(a-acety1amino-5,5- dimethyl 'y acetoxybutyrylamino) -propionate thus formed.

11. A method for the preparation of ethyl 5'- (a. acetylamino-5,5-dimethyl-' -acetoxybutyrylamino) -pr0pionate which comprises subjecting to hydrogenolysis ethyl 5' (a. carbobenzoxyamino-5,5-dimethyl 'y hydroxybutyrylamino) propionate in an ethanol-hydrochloric acid medium thereby obtaining ethyl 5-(a-amino-5,5- dimethyl 'y hydroxybutyrylamino) -propionate hydrochloride as a product, reacting said product with acetic anhydride in a pyridine solution and recovering the ethyl 5'-(a-acetylamin0-5,5-dimethyl-' -acetoxybutyrylamino) -propionate thus formed.

12. A method for the preparation of,ethyl 5'- (a acetylamino-5,5-dimethyl-- -acetoxybutyrylamino) -propionate which comprises reacting ethyl'5' (a amino 5,5 dimethyl-' -hydroxybutyrylamino) propionate hydrochloride with acetic anhydride in a pyridine solution and recovering the ethyl 5-(a-acetylamino-5.5-dimethyl- 'y-acetoxybutyrylamino) -propionate thus formed.

13. A method for synthesizing ethyl 5'-(a-carbobenzoxyamino 5;5 dimethyl 'y hydroxybutyrylamino) -propionate which comprises reacting a. carbobenzoxyamino 5,5 dimethyl-'y-butyrolactone with ethyl-5-amino propionate and recovering the ethyl 5'-( 1:-carbobenzoxyamino-v 5,5 dimethyl 'y-hydroxybutyrylamino) -propionate thus formed.

KARL FOLKERS. FREDERICK W. HOLLY.

No references cited. 

1. AS A NEW PHYSIOLOGICALLY ACTIVE CHEMICAL COMPOUND ETHYL B''-(A-AMINO-B,B- DIMETHYL - Y HYDROXYBUTYRYLAMINO) - PROPIONATE AND STRONG MINERAL ACID SALTS THEREOF. 